Emerging resistance to existing antibiotics is rapidly developing as a crisis of global proportions, especially for Staphylococcus aureus, Streptococcus pyogenes, and Streptococcus pneumonia infections. Pathogenic bacteria can transmit genes coding for antibiotic resistance both vertically (to their progeny) and horizontally (to neighboring bacteria of different lineages), and as a result antibiotic resistance can evolve quickly, particularly in nosocomial (hospital) settings. See, e.g., Wright, Chem. Commun. (2011) 47:4055-4061. This year, >99,000 people will die in the U.S. from healthcare-associated infections, more than all casualties from car accidents, HIV, and breast cancer combined, creating an estimated burden of up to $45 billion in U.S. healthcare costs. See, e.g., Klevens et al., Public Health Rep (2007) 122:160-166. The current crisis is exacerbated by the fact that most major pharmaceutical companies have essentially abandoned research in the development of new antibiotics. See, e.g., Projan Curr. Opin. Microbiol. (2003) 6: 427-430. The current rate of introduction of new antibiotics does not adequately address growing resistance, and with the ease of international travel and increasing population densities, the need for innovation in the field has never been higher.
The macrolides are one of the few major clinically important classes of antibiotics for which the only practical access has been through semi-synthesis, or chemical manipulation of structurally complex fermentation products, in routes as long as 16 steps. See, e.g., Paterson, Tetrahedron (1985) 41:3569-3624; Omura, Ed., Macrolide Antibiotics: Chemistry, Biology, and Practice, Second Edition; Academic Press, 2002. The macrolide class of antibiotics has proven safe and effective in the battle against pathogenic bacteria since the discovery of erythromycin over 60 years ago. See, e.g., Wu et al., Curr. Med. Chem. (2001) 8, 1727-1758. Erythromycin displays a spectrum of antibacterial activity against Gram-positive bacteria similar to that of penicillin but has a lesser propensity to induce allergic interactions, and has been routinely prescribed for upper and lower respiratory tract infections and urogenital infections. See, e.g., Washington et al., Mayo. Clin. Proc. (1985) 60:189-203; Washington et al., Mayo. Clin. Proc. (1985) 60:271-278. However, erythromycin is known to undergo acid-promoted internal ketalization (cyclization of the C6 and C12 hydroxyl groups onto the C9 ketone) in the gut, which leads to adverse gastrointestinal events. See, e.g., Kurath et al., Experientia (1971) 27:362. Second-generation macrolide antibiotics clarithromycin and azithromycin addressed issues of acid instability and were prepared semi-synthetically in 4-6 steps from erythromycin, which is readily available through large-scale fermentation. See, e.g., Ma et al., Curr. Med. Chem. (2011) 18:1993-2015; Wu et al., Curr. Pharm. Des. (2000) 6:181-223; Ma et al., Mini-Rev. Med. Chem. (2010) 10:272-286; Asaka et al., Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) (2003) 3:961-989; Morimoto et al., J. Antibiot. (1990) 43:286-294; Morimoto et al., J. Antibiot. (1984) 37:187-189; Watanabe et al., J. Antibiot. (1993) 46: 1163-1167; Watanabe et al., J. Antibiot. (1993) 46:647-660; Bright et al., J. Antibiot. (1988) 41: 1029-1047; Djokic et al., J. Antibiot. (1987) 40:1006-1015; Mutak et al., J. Antibiot. (2007) 60: 85-122; and Retsema et al., Antimicrob. Agents Chemother. (1987) 31:1939-1947. Azithromycin has been shown to exhibit markedly improved efficacy against Gram-negative organisms, and has a longer half-life and higher tissue distribution than the other macrolide antibiotics, thought to correlate with its 15-membered ring containing a tertiary amine. See, e.g., Ferwerda et al., J. Antimicrob. Chemother. (2001) 47:441-446; Girard et al., Antimicrob. Agents Chemother. (1987) 31:1948-1954. The natural product tylosin, a 16-membered macrolide used in veterinary medicine, has been shown by X-ray crystallography to occupy the same binding pocket as erythromycin and azithromycin, suggesting that there is a high tolerance for variability in ring size and composition of the macrocycle.
The three primary causes of resistance to macrolides in bacterial organisms are ribosome methylation encoded by erm genes, mutations in ribosomal RNA or peptides, and cell efflux mediated by mef and msr genes. See, e.g., Leclercq et al., Antimicrob. Agents Chemother. (1991) 35:1273-1276; Leclercq et al., Antimicrob. Agents Chemother. (1991) 35:1267-1272; Weisblum, Antimicrob. Agents Chemother. (1995) 39:577-585; Vester et al., Antimicrob. Agents Chemother. (2001) 45:1-12; Prunier et al., Antimicrob. Agents Chemother. (2002) 46:3054-3056; Li et al., J. Antimicrob. Chemother. (2011) 66:1983-1986; Sutcliffe et al., Antimicrob. Agents Chemother. (1996) 40:1817-1824; Wondrack et al., Antimicrob. Agents Chemother. (1996) 40: 992-998. Ketolides such as telithromycin and solithromycin defeat the efflux mechanism of resistance by replacement of the C3 cladinose sugar with a carbonyl group (hence the name “ketolides”), and are thought to exhibit greatly increased binding by virtue of favorable interactions between the novel aryl-alkyl sidechain and the ribosome. See, e.g., Ma et al., Curr. Med. Chem. (2011) 18:1993-2015; Ma et al., Mini-Rev. Med. Chem. (2010) 10:272-286. Despite greatly improved ribosomal binding, ketolides such as telithromycin and solithromycin have not addressed several of the newest forms of macrolide resistance that have evolved in nosocomial settings, especially ribosome methylation and RNA point mutations.